Metabolomic profiles are reflective of hypoxia-induced insulin resistance during exercise in healthy young adult males

Hypoxia-induced insulin resistance appears to suppress exogenous glucose oxidation during metabolically matched aerobic exercise during acute (<8 h) high-altitude (HA) exposure. However, a better understanding of this metabolic dysregulation is needed to identify interventions to mitigate these effects. The objective of this study was to determine if differences in metabo-lomic profiles during exercise at sea level (SL) and HA are reflective of hypoxia-induced insulin resistance. Native lowlanders (n = 8 males) consumed 145 g (1.8 g/min) of glucose while performing 80-min of metabolically matched treadmill exercise at SL (757 mmHg) and HA (460 mmHg) after 5-h exposure. Exogenous glucose oxidation and glucose turnover were determined using indirect calorimetry and dual tracer technique ([C-13]glucose and [6,6-H-2(2)]glucose). Metabolite profiles were analyzed in serum as change (Delta), calculated by subtracting postprandial/exercised state SL (Delta SL) and HA (Delta HA) from fasted, rested conditions at SL. Compared with SL, exogenous glucose oxidation, glucose rate of disappearance, and glucose metabolic clearance rate (MCR) were lower (P < 0.05) during exercise at HA. One hundred and eighteen metabolites differed between Delta SL and Delta HA (P < 0.05, Q < 0.10). Differences in metabolites indicated increased glycolysis, tricarboxylic acid cycle, amino acid catabolism, oxidative stress, and fatty acid storage, and decreased fatty acid mobilization for Delta HA. Branched-chain amino acids and oxidative stress metabolites, Delta 3-methyl-2-oxobutyrate (r = -0.738) and Delta gamma-glutamylalanine (r = -0.810), were inversely associated (P < 0.05) with Delta exogenous glucose oxidation. Delta 3-Hydroxyisobutyrate (r = -0.762) and Delta 2-hydroxybutyrate/2-hydroxyisobutyrate (r = -0.738) were inversely associated (P < 0.05) with glucose MCR. Coupling global metabolomics and glucose kinetic data suggest that the underlying cause for diminished exogenous glucose oxidative capacity during aerobic exercise is acute hypoxia-mediated peripheral insulin resistance.

Automated summary

This study reveals that during metabolically matched aerobic exercise in acute high-altitude conditions, exogenous glucose oxidation is decreased and insulin resistance is weakened, impacting metabolic profiles. These differences indicate that acute hypoxia-mediated insulin resistance may be the underlying cause for diminished exogenous glucose oxidative capacity.